DESCRIPTION (Applicant's Description): During larval development Drosophila imaginal discs grow by normal cell division, whereas most larval cells grow by hypertrophy. Analysis of the consequences of mutations in the minidiscs gene and of targeted minidiscs expression has revealed that imaginal cell proliferation, but not larval cell growth, is regulated by a diffusible factor secreted by the larval fat body that has been named minidiscs dependent growth factor or MDGF. The long term goal of the proposed project is to elucidate the mechanism by which MDGF regulates the growth of distant target tissues, the imaginal discs. In humans, there are well known factors that are secreted into the circulatory system and regulate the growth of distant target tissues. As such this research is relevant to human developmental defects such as birth defects and cancer that are associated with abnormal levels of these secreted factors. Three specific aims are addressed in this proposal. 1) Four genes have been identified as candidates for ones whose products are required in the fat body for the synthesis, activation, and/or secretion of MDGF. The first candidate gene, compact discs (cds), encodes an entirely novel protein. The hypothesis to be tested is that the CDS protein acts in the fat body downstream of minidiscs function in the pathway leading to secretion of MDGF. The second candidate gene encodes a protein that is likely to be the regulatory subunit of the MND transporter. We will test the hypothesis that it is component of a heterodimer with MND and acts in parallel with minidiscs. The products of the two other candidate genes will be identified and their potential role will be analyzed using approaches similar to ones we apply to the study of compact discs. 2) The Imaginal Disc Growth Factors and Fat Body Derived Growth Factor will be evaluated as candidates for MDGF. 3) Mutational screens for dominant modifiers of a temperature sensitive minidiscs mutation will be used to identify the receptor for MDGF and downstream signaling components that respond to activation of the receptor in imaginal discs by causing or allowing cell proliferation. A pilot screen has yielded several putative suppressor mutations.